Calcium And Bone Flashcards
Normal: What is intracellular calcium maintained at?
Low concentration
Normal: what concentration is extra cellular calcium maintained at?
High
What allows calcium ions to bind to proteins which lets them influence key cell processes?
Reversible increases of intracellular calcium
Why is extracellular calcium high?
To allow normal bone mineralisation
To maintain normal activity of excitable tissue
Where is extracellular calcium measured about?
In blood in either serum or plasma
Does the calcium measured in plasma usually have a defined range?
Yes (will tel us what this is in exam)
What are the 2 components the calcium range is made up of?
Ionised Ca2+ which is physiologically active
Ca2+ which is ‘bound’ mainly to albumin and is not physiologically active
What type of calcium is actively regulated?
Ionised calcium
What is the major calcium binding protein in blood
Albumin
Will abnormal albumin concentration affect calcium binding?
Yes
Will abnormal albumin concentration affect calcium binding?
Yes
Is measuring both albumin and total calcium required to assess extracellular ionised Ca2+status
Yes
What would happen to the bound calcium if the albumin is not constant?
The bound calcium wouldn’t be constant
What would happen to the ionised calcium if the albumin is not constant?
Nothing
What are some general things that happen to calcium in the body?
Absorbed, secreted, absorbed into bones
Does calcium balance change throughout life?
Yes
What does growth of bone require from calcium?
A positive calcium balance
Calcium balance throughout life - adulthood would ideally be associated with what?
Calcium in = calcium out
What is the ageing process associated with?
Slow phase negative calcium leading to loss of bone density
When does bone loss accelerate?
After menapause
How much body weight does the skeleton take up?
17%
What are the functions of bones (list)
- Support of the body
-Protection of organs
-Leverage system for movement
-Site for hematopoiesis
-Endocrine function (fibroblast growth factor-23;osteocalcin)
-Regulation of mineral homeostasis
What are two different types of bones?
Trabecular bone and cortical bone
What do osteoblasts do?
They make bins
What do osteoclasts do?
Reabsorb bone
What do osteocytes do?
It is the mechanosensor cell and most abundant cell in bones
Bone formation by osteoblasts?
Osteoblast precursors on the outside
Ob cells need to be mature cells and stimulated to make new bones - once they have been they make a calcified bone matrix.
Bone matrix mineralisation - what is the mineral component?
hydroxyapatite
What is hydroxyapatite?
Tiny crystals surround collagen fibres
- Provides rigidity, resistance to compression
What is mineralisation of osteoid dependant on?
calcitriol
What happens if there is a calcitriol deficiency?
Deficiency results in failure to mineralise
Leads to rickets in children, osteomalacia in adults
How long does full mineralisation take?
Several Months
What is Expressed on surface of differentiated osteoblasts; also released into extracellular fluid and circulation (bone formation marker)
Alkaline phosphatase (ALP)
What does alp do?
Releases inorganic phosphate ions (PO43-) from diverse molecules (hydrolysis)
What is the 2 ways alp promotes mineralisation?
- By increasing the local concentration of inorganic phosphate ions
- by hydrolysing pyrophosphate, a key inhibitor of mineralisation
What is the trabecular use for?
Metabolism, endocrine function
How do osteoblasts tell the bone to be made?
They sense microfibres and can then signal to the bone cells to make more cells
What can high alp mean?
There is something going on in the Bone or in the liver
Bone reabsorption - what are osteoclasts?
Multinucleated cell formed by fusion of promonocytic precursors present in marrow and circulation
The border adjacent to bone surface secretes hydrogen and enzymes.
Bone reabsorption - what is needed for hydrogen generation?
High levels of carbonic anhydride
What is the role of RANK - RANKL in osteoclast biology and function?
Activates osteoclast cells so reabsorption can take place
What is RANK?
receptor on osteoclast precursors
What does RankL do to RANK?
ligates to rank which activates them o thye can act on the surface and make mature osteoclasts which will secrete acid and enzymes which can chew the bone
What is Osteopetrosis and what does it cause?
Disease which causes an increase in bone density due to dysfunctional osteoclasts
In osteopatrosis why does dysfunctional osteoclasts cause an increase in bone density?
Causes pits of reabsorption which stimulates bone formation
In osteopetrosis what is wrong with the new bone formed?
The new bone layed is dysfunctional - brittle and hard making them more fragile
What is the mechanism behind osteopetrosis?
Due to failure of matrix degradation by osteoclasts - a failure of the protein pump which stops hydrogen leaving the cell, could also be because of chloride not being able to cross the cell and therefore upsetting the acid balance.
Bone remodelling cycle?
Bone absorbed and then bone formed
Why do we need bone metabolism?
Growth
respond to different mechanical requirements
repair damage - fractures, micro or large
maintenance
calcium defecet
is bone formation in balance in healthy people?
yes
What would cause bone disease?
An inbalance in bone absorption and formation
What is osteoperosis
common in menopause as bones need eostrogen
What causex pagets disease?
overactive osteoclasts and therefore bone absorption
What are the two hormones which keep calcium regulated?
PTH and calcitriol (vitamin D)
What are the principle organs for calcium regulation?
gut, bone and kidney
Is PTH a peptide and is it easily degraded?
Yes
What does PTH do?
regulates ionised calcium levels in the blood every minute
Where is PTH secreted from?
parathyroid gland
When is PTH repsonse increased?
When calcium is falling so the calcium can be restored
What happens to PTH when there is lots of calcium in the blood?
Its decreased.
What senses the calcium levels to regulate PTH?
calcium receptors
How is g-protein couple receptors activated?
By binding calcium
What are the main actions of PTH?
Stimulates ca efflux from bone and release of ca
Stimulates renal tubular reabsorption of ca
Stimulates formation of calcitriol (indirectly) promoting intestinal absorption of Ca2+
Promotes phosphate and bicarbonate loss from the kidney (proximal tubule)
What sould you remember about phosphate and calcium balance when talking about PTH?
calcium goes into cell phosphate goes out
How does PTH stimulate vitamin D
Helps absorption of calcium in the gut
Look at the feedback of vitamin D
what is calcitonin?
polypeptide secreted in response to rising calcium from the parafollicular or c-cells of the thyroid gland
What does calcitonin do?
Principal action is to reduce osteoclast activity and has no clear role in calcium homeostasis
Can you use calcitonin therapeutically to lower serum calcium levels?
Yes - this would be a good thing to suggest in a calcium question
Can calcitonin be used as a tumour marker?
yes in thyroid or breast cancers
What is vitamin D a source of?
calcitriol
What is vitamin D?
A steroid structure, fat soluble vitamin
How is vitamin D produced?
action of UV light on skin precursors
can vitamin D be taken up through the gut?
yes
What are some dietary sources of vitamin D?
Oily fish, eggs, butter, margarine
What is cholalciferol?
inactive state of vitamin D
How is cholecalciferol activated and it produces what when activated?
activated by liver or kidneys to produce calcitriol (active vitamin D)
What does vitamin D do?
Is a hormone that acts within the kidney - it acts through receptor and is crucial in longer term maintainence of calcium and is required for normal bone growth and mineralisation
How is Vitamin D synthesised?
The precursor sterol is turned into vitamin D by UV light
How is vitamin D synthesised?
It circles in the liver where the enxyme 25-hydroxylase hydroxilases it to 25-hydroxy vitamin D which can then function without input from the blood calcium status or PTH.
What is the best screening test for vitamin D adequacy?
25-vitamin D - this is stable but is not active
What happens to 25-vitamin D to make it active?
It goes to the kidney where its hydroxylated by 1-alpha-hydroxylase to 1,25 vitamin D (calcitriol)
What is Renal 1α-hydroxylase is regulated by?
PTH but calcium can affect its activity
How do you inactive vitamin D?
Hydroxylate the 24 region
Mechanism of calcitriol action?
Calcitriol binds to a single vitamin D receptor this complex acts through a vitamin D reponsive elements
How is the mechanism of calcitriol action done in the intestine?
calcium-binding protein (calbindin-D9k) is synthesised which promotes absorption ofboth calcium and phosphate
What is the mechanism of calcitriol action in the bone?
stimulates osteoblast differentiation andosteoclast activation via RANK ligand (RANKL) formation in osteoblasts
What are the actions of calcitriol?
promotes gut absorption of calcium andphosphate (requires new protein synthesis)
Calcitriol, in concert with PTH, stimulates osteoclasts and efflux of Ca2+ from bone
Calcitriol, in concert with PTH, increases renal Ca2+ reabsorption
Maintenance of both calcium and phosphate levels essential for hydroxyapatite formation andnormal bone mineralisation
Calcitriol deficiency has major effects on bonemineralisation (low calcitriol, high PTH)
Calcitriol vs PTH?
Both maintain ionised Ca2+
PTH responsible for minute-by-minute plasma Ca2+ regulation
Calcitriol responsible for longer term plasma Ca2+ regulation
PTH tends to decrease plasma phosphate
Calcitriol raises plasma phosphate
What happens if there is a active vitamin D deficiency?
less calcium being taken up causing bones to be absorbed.
What are the interactions between PTH and calcitriol - co-operativity?
PTH promotes 1α-hydroxylase activity
PTH and calcitriol both required in vivo for osteoclast activation and distal tubular Ca2+ reabsorption
Calcitriol deficiency may impair PTH action
Interaction between PTH and calcitriol - what is the limitation of action?
Calcitriol stimulates 24-hydroxlase (promotes its own inactivation)
Calcitriol can switch off PTH gene transcription via VDR in parathyroid cells, limiting PTH action
